Unraveling the genetic architecture of major depressive disorder: merits and pitfalls of the approaches used in genome-wide association studies.

To identify genetic risk loci for major depressive disorder (MDD), two broad study design approaches have been applied: (1) to maximize sample size by combining data from different phenotype assessment modalities (e.g. clinical interview, self-report questionnaires) and (2) to reduce phenotypic heterogeneity through selecting more homogenous MDD subtypes. The value of these strategies has been debated. In this review, we summarize the most recent findings of large genomic studies that applied these approaches, and we highlight the merits and pitfalls of both approaches with particular attention to methodological and psychometric issues. We also discuss the results of analyses that investigated the heterogeneity of MDD. We conclude that both study designs are essential for further research. So far, increasing sample size has led to the identification of a relatively high number of genomic loci linked to depression. However, part of the identified variants may be related to a phenotype common to internalizing disorders and related traits. As such, samples containing detailed clinical information are needed to dissect depression heterogeneity and enable the potential identification of variants specific to a more restricted MDD phenotype. A balanced portfolio reconciling both study design approaches is the optimal approach to progress further in unraveling the genetic architecture of depression.

Impact of severe mental illness on cancer stage at diagnosis and subsequent mortality: A population-based register study.

BACKGROUND: Excess mortality in individuals with severe mental illness (SMI) is often explained by physical comorbidity and suboptimal healthcare. Cancer is a prevalent cause of death, and tumour stage at diagnosis is a strong predictor of mortality. We aimed to study cancer incidence, disease stage at diagnosis and subsequent mortality in individuals with SMI compared to individuals without SMI. METHODS: The entire Danish population was followed in 1978-2013 using nationwide registries. Cancer incidence and subsequent mortality stratified by disease stage were compared in individuals with and without SMI. Cox regression was used to estimate incidence rate ratios (IRR) and mortality rate ratios (MRR). Cancer was examined overall and grouped by major aetiological factors. RESULTS: The overall cancer incidence rate was lower in males with SMI than in males without SMI; IRR = 0.89 (95% CI: 0.85-0.94), but rates were similar in females with SMI and without SMI; IRR = 1.03 (95% CI: 0.99-1.07). The overall mortality rate was higher in individuals with SMI than those without; MRR = 1.56 (95% CI: 1.48-1.64) for males and MRR = 1.49 (95% CI: 1.43-1.56) for females. Incidence rates and mortality rates showed similar estimates when stratified by tumour stage and aetiology. CONCLUSIONS: We found lower cancer incidence in males with SMI compared to males without SMI and similar incidence in the two groups of women. Higher subsequent mortality was found in both sexes with SMI. The excess mortality was not explained by more advanced stages of cancer; future studies should evaluate the effect of cancer treatment and rehabilitation.

5-HTTLPR and use of antidepressants after colorectal cancer including a meta-analysis of 5-HTTLPR and depression after cancer.

The serotonin-transporter-linked polymorphic region (5-HTTLPR) is one of the most extensively investigated candidates to be involved in gene-environment interaction associated with depression. Nevertheless, the interaction remains controversial. In an original study, we tested the hypothesis that risk for use of antidepressants following a diagnosis of colorectal cancer is associated with bi- and triallelic genotypes of 5-HTTLPR. In addition, in an inclusive meta-analysis, we tested the hypothesis that depression following a diagnosis of cancer is associated with biallelic 5-HTTLPR genotype. We created an exposed-only cohort of 849 colorectal cancer patients from the Danish Diet, Cancer and Health cohort study. The hypothesized association was investigated with Cox regression models and competing risk analyses. Five studies comprising a total of 1484 cancer patients were included in the meta-analysis. Nationwide registries provided information on dates of diagnosis of colorectal cancer and use of antidepressants. Unadjusted odds ratios of depression according to the biallelic 5-HTTLPR genotype were included in the meta-analysis. 5-HTTLPR genotypes were not associated with use of antidepressants after colorectal cancer. Estimated hazard ratios ranged 0.92-1.08, and we observed no statistically significant associations across biallelic and triallelic genotypes in crude as well as adjusted models. The meta-analysis showed no statistically significant associations of 5-HTTLPR biallelic genotype with depression after cancer. Our findings in an original study and a meta-analysis do not support the hypothesis of an association between the 5-HTTLPR genotype and depression after cancer.

Who are the cancer survivors? A nationwide study in Denmark, 1943-2010.

BACKGROUND: No nationwide studies on social position and prevalence of comorbidity among cancer survivors exist. METHODS: We performed a nationwide prevalence study defining persons diagnosed with cancer 1943-2010 and alive on the census date 1 January 2011 as cancer survivors. Comorbidity was compared by social position with the non-cancer population. RESULTS: Cancer survivors composed 4% of the Danish population. Somatic comorbidity was more likely among survivors (OR 1.59, 95% CI 1.57-1.60) and associated with higher age, male sex, short education, and living alone among survivors. CONCLUSIONS: Among cancer survivors, comorbidity is common and highly associated with social position.